Amino Acid Derivatives for the Treatment of Inflammatory Diseases

Abstract

The present disclosure provides certain amino acid derivatives that inhibit NF-kB activation and are therefore useful for the treatment of inflammatory diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

What is claimed: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 n is 0, 1, or 2; 
 dashed line is an optional bond; 
 Het is heteroaryl optionally substituted with R a , R b , and/or R c  independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl; 
 R 1  is hydrogen or alkyl; 
 R 2  is hydrogen or alkyl; 
 R 3  is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl or heteroaryl by itself as part of aralkyl or heteroaralkyl is optionally substituted with R d , R e , and/or R f  independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino; 
 R 4  is hydrogen or alkyl; and 
 R 5  is —C(O)R 6  where R 6  is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl wherein aryl or heteroaryl by itself or as part of aralkyl or heteroaralkyl is optionally substituted with R g , R h , and/or R i  independently selected from alkyl, alkoxy, aminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, halo, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino; or 
 R 4  and R 5  together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocycloamino ring; or 
 a pharmaceutically acceptable salt thereof. 
 
       
     
     
         2 . The compound of  claim 1  wherein the compound has structure (IA): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1  wherein the compound has structure (IB): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of any one of  claims 1 - 3  wherein n is 1, 2, or 3. 
     
     
         5 . The compound of any one of  claims 1 - 4  wherein n is 1. 
     
     
         6 . The compound of any one of  claims 1 - 3  wherein n is 0 or 2. 
     
     
         7 . The compound of any one of  claims 1 - 3  wherein n is 0. 
     
     
         8 . The compound of any one of  claims 1 - 3  wherein n is 2. 
     
     
         9 . The compound of any one of  claims 1 - 8  wherein R 4  is hydrogen or alkyl and R 5  is —C(O)R 6  where R 6  is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl wherein aryl or heteroaryl by itself or as part of aralkyl or heteroaralkyl are optionally substituted with R g , R h , and/or R′ independently selected from alkyl, alkoxy, aminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, halo, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino. 
     
     
         10 . The compound of  claim 9  wherein R 5  is aryl or heteroaryl optionally substituted with R g , R h , and/or R i . 
     
     
         11 . The compound of  claim 9  wherein R 5  is aralkyl or heteroaralkyl optionally substituted with R g , R h , and/or R i . 
     
     
         12 . The compound of  claim 9  wherein R 5  is phenyl optionally substituted with R g , R h , and/or R i . 
     
     
         13 . The compound of any one of  claims 1  to  12  wherein R g  is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, or cyano and R h  and R′ are independently selected from alkyl, alkoxy, aminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, or sulfonylamino. 
     
     
         14 . The compound of any one of  claims 1  to  12  wherein R g , R h  and R i  are independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, acylamino, preferably, methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, hydroxy, acetylamino, butanoylamino, and pentanoylamino. 
     
     
         15 . The compound of any one of  claims 1  to  8  wherein R 4  and R 5  together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocycloamino ring. 
     
     
         16 . The compound of any one of  claims 1  to  15  wherein R 1  and R 2  are independently hydrogen or methyl, preferably hydrogen. 
     
     
         17 . The compound of any one of  claims 1  to  16  wherein when both R 1  and R 2  are alkyl, they are not bound to the same ring carbon. 
     
     
         18 . The compound of any one of  claims 1  to  17  wherein Het is pyridinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, or indolyl, each ring optionally substituted with R a , R b , and R c  independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl. 
     
     
         19 . The compound of any one of  claims 1  to  17  wherein R a , R b , and R c  independently selected from methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, or dimethylamino. 
     
     
         20 . The compound of any one of  claims 1  to  17  wherein Het is pyridin-2-yl. 
     
     
         21 . The compound of any one of  claims 1  to  20  wherein R 3  is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl wherein aryl or heteroaryl by itself or in aralkyl and heteroaralkyl is optionally substituted with R d , R e , and/or R f  independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino. 
     
     
         22 . The compound of any one of  claims 1  to  20  wherein R 3  is hydrogen or alkyl, preferably methyl, ethyl, propyl, isopropyl, sec-propyl, n-, sec, iso, tert-butyl. 
     
     
         23 . The compound of any one of  claims 1  to  20  wherein R 3  is aralkyl optionally substituted with R d , R e , and/or R f , preferably R 3  is benzyl or phenethyl, more preferably benzyl optionally substituted with R d , R e , and/or R f , even more preferably R 3  is benzyl. 
     
     
         24 . The compound of any one of  claims 1  to  20  wherein R 3  is cycloalkylalkyl optionally substituted with R d , R e , and/or R f , preferably R 3  is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl optionally substituted with R d , R e , and/or R f . 
     
     
         25 . The compound of any one of  claims 1  to  20  wherein R 3  is heteroaralkyl (e.g., thienylmethyl, furanylmethyl, pyridinylmethyl, quinolinylmethyl, isoquinolinylmethyl, indolylmethyl, or indazolylmethyl) optionally substituted with R d , R e , and/or R f . 
     
     
         26 . The compound of any one of  claims 1  to  20  wherein R 3  is hydroxyalkyl, alkoxyalkyl, aminoalkyl, preferably R 3  is hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, aminomethyl, or aminobutyl. 
     
     
         27 . The compound of any one of  claims 1  to  26  wherein the stereochemistry at carbon to which R 3  is attached is (S). 
     
     
         28 . The compound of any one of  claims 1  to  26  wherein the stereochemistry at carbon to which R 3  is attached is (R). 
     
     
         29 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 28  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         30 . A method of treating a disease treatable by inhibiting NF-kB activation comprising administering to a patient in need thereof, the pharmaceutical composition of  claim 29 . 
     
     
         31 . The method of  claim 30  wherein the disease is an inflammatory disease. 
     
     
         32 . The method of  claim 31  wherein the disease is selected from the group consisting of autoimmune disease, pain, allergies, asthma, chronic obstructive pulmonary disease and sepsis. 
     
     
         33 . The method of  claim 30  wherein the disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet's disease, tuberculosis, Crohn's disease, colitis, Pagett's disease, pancreatitis, periodonitis, inflammatory lung disease, and lupus nephritis.